The overall goal of this project is to understand the role of poly(ADP- ribose) polymerase in the pathogenesis and pathology of neuronal injury following excitotoxicity and ischemia-reperfusion injury. The Program represents a multi-disciplinary, mechanistic approach involving interactive, productive investigators with complimentary areas of expertise who have a long-term commitment to studies of neuronal injury. This Program will integrate the activities of various disciplines such that the interrelationships will result in a greater scientific contribution than could be achieved if each projects were pursued individually. The Program has two theme: first, the molecular biology and biochemistry of the activation of activity of poly(ADP-ribose) polymerase which results in neuronal damage. Wild-type and mutant mice will be used to determine the primary activations of poly (ADP-ribose) polymerase and to determine the secondary targets of poly (ADP-ribose) polymerase activity which may mediate or contribute to neuronal injury. Second, molecular, cell biologic, neuropathologic and neurobehavioral approaches will be used to determine which functional domains of poly(ADP-ribose) polymerase are important to target to provide neuroprotection State of the art molecular, neuropathological, physiological and neurobehavioral approaches are used throughout the Program. The Program has several important strengths. The investigators have a long history of interactive studies of neuronal injury and mechanisms to limit injury in the nervous system. Several strong, young investigators with critical novel expertise have been integrated into the Program. The investigators are leaders in the field of neuronal injury and ischemia. Sophisticated experimental approaches are used to gain insight into this noel mediator of neuronal death. We believe that our multi-disciplinary approach has the capacity to produce unique information concerning the mechanism of neuronal injury mediated by poly(ADP-ribose) polymerase and determine the mechanisms of the profound neuroprotection observed in the poly(ADP-ribose) polymerase knockout mice. The Program consists of three projects: 1) PARP in Excitotoxic and Apoptotic Neuronal Injury; 2) Excitotoxins and PARP in Striatal Neuronal Vulnerability; 3) PARP in Focal Cerebral Ischemia; and is supported by three core facilities: A) Administrative; b) Transgenic Mouse; and C) Viral Gene Transfer.